Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[N+:18]([O-])([OH:20])=[O:19].O>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([O:11][CH3:12])=[O:10])=[CH:6][C:7]=1[N+:18]([O-:20])=[O:19]
Reactant: COC(=O)C(c1ccc(O)cc1)C1CCCC1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(c1ccc(O)c([N+](=O)[O-])c1)C1CCCC1
Reaction time: 0.25 h
Yield: 71 %

Procedure:
22.9 g (0.1 mol) of methyl 2-(4-hydroxyphenyl)-2-cyclopentyl-acetate are dissolved in 50 ml of CH2Cl2 and added dropwise at 5° C. to a solution of 50 ml of conc. HNO3 /50 ml of H2O. The mixture is stirred for 15 min, then 100 ml of H2O are added and the organic phase is separated off. The aqueous phase is extracted three times with 50 ml of CH2Cl2, and the organic phases are washed 5 times with water, dried, concentrated to a small volume and filtered through silica gel. After concentration, the product is obtained in 71% yield (20 g). The product is further processed in crude form.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([CH3:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.CO>[C].[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([CH3:13])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Cc1ccc(N)cc1
Yield: 67.6 %

Procedure:
A solution of 1-(4-nitrophenyl)acetone (2.00 g, 11.2 mmol), 10% palladium-carbon (200 mg), methanol (20 ml) and tetrahydrofuran (10 ml) was stirred under a hydrogen atmosphere for 12 hours. Insolubles were filtered off to obtain the desired product (1.13 g, 67.6%) as an oil.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)=O.C([Li])CCC.[Cl-].[Zn+2:18].[Cl-]>O1CCCC1.CCCCCC.C(O)C>[C:1]1([C:7]#[C:8][Zn:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Zn+2]
Reactant: C#Cc1ccccc1
Agent: O=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Zn]C#Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
The flask was charged with 120 mg (1.1 mmol) of phenylacetylene and 4 mL of tetrahydrofuran, and the flask was cooled to −78° C. in a cooling bath with ethanol and dry ice. Thereafter, 0.65 mL (1.0 mmol) of a 1.56 mol/L hexane solution of n-butyllithium was slowly added over a period of 20 minutes. After stirring the mixture at −78° C. for 30 minutes, a suspension of 140 mg (1.0 mmol) of zinc chloride in 1 mL of tetrahydrofuran was added thereto. The mixture was stirred at −78° C. for additional 1 hour, thereafter the cooling bath was removed, and the mixture was allowed to stand upto room temperature. The resulting solution was used as (phenylethynyl)zinc reagent [(Ph—C≡C—ZnCl].
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:10](=[O:11])[N:9]([CH:12]3[C:18](=[O:19])[NH:17][C:15](=O)[CH2:14][CH2:13]3)[C:7](=[O:8])[C:5]=2[CH:6]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[O:19]=[C:18]1[CH:12]([N:9]2[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])[CH2:13][CH2:14][C:15](=[S:29])[NH:17]1
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: O=C1NC(=S)CCC1N1C(=O)c2ccccc2C1=O
Yield: 132.6 %

Procedure:
Compound 203 (1.14 g, 5 mmol) was suspended in CH2Cl2 (100 mL). To the mixture was added CF3COOH (10 mL) and this then was stirred at room temperature for 4 h. The solvent was evaporated to give crude 204 (1.25 g): 1H NMR (DMSO-d6) δ 11.42 (s, 1H), 8.70 (br, 2H), 4.31 (dd, J=5.4 Hz, J=13 Hz), 2.88-2.72 (m, 2H), 2.25-2.09 (m, 2H). A mixture of crude 204 (1.25 g) and phthalic anhydride (0.89 g, 6 mmol) and Et3N (1.39 ml, 10 mmol) in THF (150 mL) was refluxed for two days. The reaction mixture was concentrated and the residue was crystallized from ethyl acetate to give thalidomide (201) (0.89 g, 69%) as white crystals; mp 276° C. (lit. 276-279° C.). A mixture of thalidomide 201 (258 mg, 1 mmol) and Lawesson's reagent (222 mg, 0.55 mmol) in toluene (50 ml) was stirred at reflux for 12 h; thereafter, solvent was removed under vacuum. The resulting residue was purified by column chromatography using CH2Cl2 as the eluent to afford compound 205 (200 mg, 73%) as a yellow solid: mp 225-226° C.; 1H NMR (DMSO-d6) δ 12.83 (s, 1H, NH), 8.00-7.92 (m, 4H, Ph), 5.32 (dd, J=5.6 Hz, J=12.9 Hz, 1H, H-3′), 3.28-3.25 (m, 2H, H-5′), 2.60-2.54 (m, 1H, H-4′), 2.17-2.10 (m, 1H, H-4′); 13C NMR (DMSO-d6) δ 208.7 (C-6′), 165.3 (C-2′), 165.2 (C-1 & C-3), 133.1 (C-5 & C-6), 129.3 (C-3a, C-7a), 121.7 (C-4 & C-7), 46.9 (C-3′), 38.9 (C-5′), 21.79 (C-4′); MS (CI/CH4) m/z 274 (M+); Anal. (C13H10N2O3S) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:4]=1[C:5](O)=[O:6].O=S(Cl)[Cl:15]>>[Cl:12][C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([Cl:15])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(Cl)cc1C(=O)O
Product: COc1ccc(Cl)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-methoxy-5-chlorobenzoic acid (0.22 g, 1.2 mmol) in 10 mL of SOCl2 was warmed to reflux and was allowed to stir for 2 hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The crude material was diluted with 5 mL of toluene and concentrated under reduced pressure. This dilution with toluene and concentration was repeated two additional times to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 3.82 (s, 3H), 7.16 (d, J=8.8 Hz, 1H), 7.49-7.59 (m, 1H), 7.61 (d, J=2.7 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][CH:8]=1.[NH2:17][C:18](N)=[O:19].O>C(O)(=O)C>[F:15][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:10][CH2:11][C:12](=[O:14])[NH:17][C:18]2=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: NC(N)=O
Reactant: O=C(O)CCNc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCN(c2cccc(C(F)(F)F)c2)C(=O)N1
Yield: 67.7 %

Procedure:
A solution of 3-(3-trifluoromethylphenylamino)propanoic acid (2.0 g) (prepared in Reference Example 95) and urea (1.0 g) in acetic acid (20.0 ml) was stirred with heating under reflux for seven hours. To the reaction mixture was water (50 ml) and the resulting mixture was extracted with ethyl acetate (30 ml×3). The organic layer was washed with water (20 ml×2) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 1-(3-trifluoromethylphenyl)dihydropyrimidin-2,4(1H,3H)-dione (1.5 g).
Reaction SMILES: O.[N-:2]=[N+:3]=[N-:4].[Na+].[CH2:6]([Sn:10](Cl)([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9]>COC(C)(C)C>[CH2:15]([Sn:10]([N:2]=[N+:3]=[N-:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Yield: 64.3 %

Procedure:
Into 40 ml of distilled water was added 9.99 g of sodium azide (0.154 mol, 10.0 equiv), 30 ml tert-butyl methyl ether, and 5.0 g (0.0154 mol, 1.0 equiv) tributyltin chloride. The resultant mixture was stirred at room temperature for one hour. Carbon 13 NMR of an aliquot taken at this point showed absence of the starting tributyltin chloride. Therefore, the organic layer, after being separated from the aqueous layer, was dried over anhydrous sodium sulfate, filtered, concentrated, and distilled to afford 3.29 g (65%) of the desired product (bp.=115°-117° C./0.4 mm): 13C NMR δ27.8, 27.0, 15.2, 13.6.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]([C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1)[CH2:11][CH2:10][CH2:9]2.[Cl:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:38][CH3:39])[CH2:28][CH2:27]1>CN(C)C=O>[ClH:22].[ClH:22].[ClH:22].[CH3:39][O:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[N:29]1[CH2:28][CH2:27][N:26]([CH2:25][CH2:24][CH2:23][O:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=2)[CH2:11][CH2:10][CH2:9]3)[CH2:31][CH2:30]1
Reactant: COc1ccccc1N1CCN(CCCCl)CC1
Reactant: O=C(c1cccnc1)N1CCCc2cccc(O)c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCOc2cccc3c2N(C(=O)c2cccnc2)CCC3)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.53 (11.0 mmol) of a 50% strength sodium hydride dispersion is introduced in portions into a solution of 2.54 g (10.0 mmol) of 8-hydroxy-1-nicotinoyl-1,2,3,4-tetrahydroquinoline in 20 ml of anhydrous dimethylformamide and the mixture is subsequently stirred at 40°-50° C. for 30 minutes. After cooling to room temperature, a solution of 4.03 g (15.0 mmol) of 1-(3-chloropropyl)-4-(2-methoxyphenyl)piperazine in 20 ml of anhydrous dimethylformamide is added dropwise and the mixture is subsequently stirred at room temperature for 16 hours. The reaction solution is poured onto 150 ml of ice-water and extracted with methylene chloride and the extracts are washed several times with water, dried and concentrated. The crude product is further purified by column chromatography on silica gel (mobile phase toluene:ethanol 9:1) and converted into the dihydrochloride as described under Example 2(a). The product thus obtained is identical to the product described under 2(a).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[C:4]([Cl:11])[C:3]=1[OH:12].C(N(CC)CC)C.[Si:20](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:33]([Si:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[O:10][CH2:9][CH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([OH:12])=[C:4]([Cl:11])[CH:5]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: OCCc1cc(Cl)c(O)c(Cl)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCCc1cc(Cl)c(O)c(Cl)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
A solution of 2,6-dichloro-4-(2-hydroxy-ethyl)-phenol (16) (2.0 g, 9.66 mmol) in methylene chloride (20 mL) at 25° C. was treated with triethylamine (1.35 mL, 9.66 mmol) and tert-butyl diphenylsilylchloride (2.48 mL, 9.66 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was diluted with methylene chloride. The organics were washed with a 1N aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95:5 petroleum ether/ethyl acetate) afforded 4-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-2,6-dichloro-phenol (70) (2.60 g, 60%) as a pale yellow oil; HRMS m/e calcd for C24H26Cl2O2Si (M+Na)+ 467.0971, found 467.0977. Exact Mass=444.1079; Molecular Weight=445.47.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:28]3[CH2:29][CH2:30][N:25]([C:22]4[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=4)[CH2:26][CH2:27]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N2CCC(=O)CC2)cc1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Product: N#Cc1ccc(N2CCC(N3CCN(c4ccc([N+](=O)[O-])cc4)CC3)CC2)cc1

Procedure:
2.5 g of 1-(4-cyanophenyl)-4-piperidone [cf. Taylor et al., Synthesis (1981) 606] and 5.2 g of 1-(4-nitrophenyl)piperazine were reacted as in Example 1.
Reaction SMILES: O.[ClH:2].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=3)=[N:13][C:12]=2[C:25]([NH:27][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)=[O:26])=[CH:7][CH:6]=1.CO>[C].[Pd].O1CCOCC1>[ClH:2].[NH2:22][C:18]1[CH:17]=[C:16]([C:14]2[NH:15][C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=3)=[C:12]([C:25]([NH:27][C:28]3[S:29][CH:30]=[CH:31][N:32]=3)=[O:26])[N:13]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc(-c2[nH]c(-c3cccc([N+](=O)[O-])c3)nc2C(=O)Nc2nccs2)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(-c2[nH]c(-c3cccc(N)c3)nc2C(=O)Nc2nccs2)cc1
Yield: 12.2 %

Procedure:
5-(4-Methoxyphenyl)-2-(3-nitrophenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide hydrochloride monohydrate (1.0 g) was suspended in a mixed solvent of methanol (100 ml) and dioxane (100 ml), and 10% palladium carbon (containing water 50%, 0.5 g) was added to carryoutcatalyticreductionatnormalpressure. Thereactionmixture was filtered and concentrated. The obtained crude crystals were recrystallized from methanol to give 2-(3-aminophenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide hydrochloride 3/2 hydrate (110 mg), melting point 245° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:21]([O-])=O)[C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:41])[NH:31][C:32]5([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[CH2:34][CH2:33]5)[CH:25]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.C(OCC)(=O)C>CN(C=O)C.[Pd]>[NH2:21][C:19]1[C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:41])[NH:31][C:32]3([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:33][CH2:34]3)[CH:25]=2)=[CH:17][C:11]2[C:12]([C:13]([NH:15][CH3:16])=[O:14])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH:20]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3cccc(C(=O)NC4(c5ccccc5)CC4)c3)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3cccc(C(=O)NC4(c5ccccc5)CC4)c3)cc12
Reaction time: 8 h

Procedure:
2-(4-Fluorophenyl)-N-methyl-6-nitro-5-(3-(1-phenylcyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide (83.3 mg, 0.152 mmol) under N2 at r.t. was dissolved in DMF (2 ml) and then added ethyl acetate (10 mL). The mixture remained as a clear light brown solution. The mixture was added palladium (97 mg, 0.045 mmol, 5%/C), flushed with H2 using a balloon, and the mixture stirred under H2 for about 8 hr. The mixture was diluted with EtOAc, and filtered through a Whatman PTFE 45 uM disk. The filtrate was evaporated. The residue was titurated with 3×1 ml Et2O (the Et2O solution was removed by using a pipette), and the light orange solid product dried (64.4 mg, 82%). 1H NMR (500 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.32 (q, J=4.17, 1H), 7.94-7.89 (overlapping m, 3H), 7.97 (s, 1H), 7.62 (d, J=6.8, 1H), 7.58 (q, 1H), 7.34 (t, J=8.70, 2H), 7.29 (t, 1H), 7.28 (d, J=7.50, 1H), 7.23 (s, 2H), 7.227 (d, J=8.00, 1H), 7.17 (t, J=7.17, 1H,), 6.99 (s, 1H), 5.09 (s, 2H), 2.79 (appeared as d, J=3.97, 3H), 1.29 (appeared as d, 4H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)+=520.39, HPLC Rt=1.497 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:10][CH2:11][C@@H:12]([CH2:16][N:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[N:19][C:18]2=[O:27])[C@H:13]([OH:15])[CH3:14])=[CH:5][CH:4]=1.N1[C-]=NN=N1.C([NH2+]C(C)C)(C)C.[CH:54]([N:57]([CH:71]([CH3:73])[CH3:72])[P:58](N(C(C)C)C(C)C)[O:59][CH2:60][CH2:61][C:62]#[N:63])([CH3:56])[CH3:55]>ClCCl>[CH:71]([N:57]([CH:54]([CH3:56])[CH3:55])[P:58]([O:59][CH2:60][CH2:61][C:62]#[N:63])[O:15][C@H:13]([CH3:14])[C@H:12]([CH2:16][N:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[N:19][C:18]1=[O:27])[CH2:11][O:10][C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:73])[CH3:72]
Reactant: CC(C)N(C(C)C)P(OCCC#N)N(C(C)C)C(C)C
Reactant: COc1ccc(C(OC[C@@H](Cn2ccc(NC(C)=O)nc2=O)[C@@H](C)O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CC(C)[NH2+]C(C)C
Agent: [c-]1nnn[nH]1
Solvent: ClCCl
Product: COc1ccc(C(OC[C@@H](Cn2ccc(NC(C)=O)nc2=O)[C@@H](C)OP(OCCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.5 %

Procedure:
To a stirred solution of 22 (1.0 g, 1.79 mmol) in 25 ml of anhydrous dichloromethane was added diisopropylammonium tetrazolide (0.35 g) followed by 0.8 g (2.66 mmol) of 2-cyanoethyl N,N,N′,N′-tetraisopropylphosphordiamidite. After being stirred at room temperature for 20 hrs the reaction was concentrated, and the residue portioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The crude phosphoramidite was precipitated twice by re-dissolving in small (˜10 ml) amount of ethyl acetate, diluting with hexane (100 ml), allowing precipitate as an oil and decanting the liquid. Drying in vacuo afforded 1.2 g (88%) of 23 as an amorphous white solid. 31P NMR (DMSO-d6): δ 148.03, 147.19.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH3:11][N:12]([CH3:17])[CH:13]=[CH:14][C:15]#[N:16].[OH-].[Na+]>ClCCCl>[C:15]([C:14](=[CH:13][N:12]([CH3:17])[CH3:11])[CH:3]=[O:4])#[N:16]
Reactant: CN(C)C=CC#N
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CN(C)C=C(C#N)C=O
Temperature: 25 °C

Procedure:
36 ml. (0.465 mole) of N,N-dimethylformamide were stirred at 0° and 36 ml. (0.392 mole) of phosphorus oxychloride were added dropwise (a salt/ice bath was used in order to keep the reaction mixture at 0°). To the stirring semi-solid, faintly colored reaction mixture was added 300 ml. of 1,2-dichloroethane. Upon warming to room temperature by means of a water bath (25°), a clear solution resulted which was cooled to -7° with an icesalt bath. A solution of 30 ml. (0.293 mole) of β-dimethylaminoacrylonitrile in 90 ml. of 1,2-dichloroethane was added dropwise keeping the temperature between -4° to -7°. The addition required about 1 hour. The cooling bath was removed and the clear amber reaction mixture allowed to come to room temperature. The reaction mixture was transferred to a 2 liter, round bottomed flask and the solvent removed in vacuo leaving a semi-solid orange colored residue. A 100 g. of ice was added to the residue which gradually dissolved with evolution of heat. The solution was transferred to a beaker and the pH adjusted to 8.4 by adding carefully 2N sodium hydroxide (815 ml. were required) to the stirred solution at 15°-20°. The resulting solution was extracted with ethyl acetate in a liquid-liquid extractor overnight. The ethyl acetate extract was cooled, the crystals which had separated were filtered off, washed with cold ethyl acetate and dried in vacuo, affording crude 2-cyano-3-dimethylaminoacrolein, as deep yellow prisms, m.p. 143°-144°. This material was dissolved in 500 ml. of hot water, treated with 2 g. of norite, the solvent removed in vacuo and the residue crystallized from absolute ethanol, producing the pure product in the form of light yellow prisms, m.p. 143°-144°.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH:13]([CH2:17]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14]2)=[CH:9][CH:8]=1>O.C(O)C>[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH:13]([CH2:17][N:1]=[N+:2]=[N-:3])[CH2:14]2)=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)CC(COS(=O)(=O)c1ccc(C)cc1)CC2
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CC(CN=[N+]=[N-])CC2

Procedure:
A solution of 3.9 g of sodium azide in 10 ml of water is added to a solution of 13.86 g (40 mmol) of p-toluenesulphonic acid (7-methoxy-1,2,3,4-tetrahydro-naphth-2-ylmethyl) ester in 200 ml of ethanol and the whole is boiled under reflux for 18 hours. After cooling, the alcohol is evaporated off under reduced pressure, water is added to the residue and extraction is carried out with dichloromethane. The organic phase is washed with water, dried over sodium sulphate and concentrated by evaporation. (7-methoxy-1,2,3,4-tetrahydro-naphth-2-yl)methylazide is obtained in the form of a yellow oil.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[C:11]1[CH:18]3[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:20][CH:12]1[CH2:13]4)[CH2:17]3)[CH2:8]2.[Br:21]N1C(=O)CCC1=O.O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:21][CH:10]1[CH:5]2[CH2:4][CH:3]3[CH2:9][CH:7]([CH2:8][CH:1]1[C:2]3=[C:11]1[CH:12]3[CH2:20][CH:16]4[CH2:15][CH:14]([CH2:19][CH:18]1[CH2:17]4)[CH2:13]3)[CH2:6]2
Reactant: C1C2CC3CC1CC(C2)C3=C1C2CC3CC(C2)CC1C3
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: BrC1C2CC3CC(C2)C(=C2C4CC5CC(C4)CC2C5)C1C3
Reaction time: 12 h

Procedure:
High selectivity for ketone introduction adjacent to double bonds can also be accomplished by selective bromination as shown in this example. 4-Bromoadamantylideneadamantane is prepared as follows. To a solution of 3 mmol (804 mg) of adamantylideneadamantane (X) in 40 ml of CH2Cl2 is added 6.6 mmol (1.175 g) of N-bromosuccinimide. The reaction mixture is refluxed and stirred for 12 hr. The reaction mixture is diluted with CH2Cl2 and ished twice with water and a saturated Na2S2O3 solution. The organic layer is dried over MgSO4 and evaporated. The yield of 4-bromoadamantylideneadamantane (XI) is over 95%). An analytically pure sample is obtained by crystallization from acetone and sublimation [115° C. (0.002 mm)]. Conversion of this intermediate to 4-ketoadamantilideneadamanatne (XII) is accomplished using the same procedure as in Example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]3[C:18]=2[CH2:19][C:20](O)=[O:21])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][CH2:31][CH3:32])=[CH:25][CH:24]=1>>[ClH:1].[CH2:31]([N:30]([CH2:29][C:26]1[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=1)[C:20](=[O:21])[CH2:19][C:18]1[N:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]2=[N:10][C:9]=1[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH3:32]
Reactant: CCNCc1ccncc1
Reactant: Cc1ccn2c(CC(=O)O)c(-c3ccc(Cl)c(Cl)c3)nc2c1
Product: CCN(Cc1ccncc1)C(=O)Cc1c(-c2ccc(Cl)c(Cl)c2)nc2cc(C)ccn12
Product: Cl
Yield: 72.1 %

Procedure:
According to the method of Example 14, 2-(3,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetic acid and N-(4-pyridinylmethyl)ethylamine were used as raw materials for synthesis, to obtain white solid powder, yield 72.1%. m.p. 250-252° C., ESI-MS m/z: 454[M+H]+, 1H NMR(DMSO-d6, 400 MHz)δ: 1.09(t, 0.7H, J=7.00 Hz), 1.25(t, 2.3H, J=7.00 Hz), 2.57(s, 2.3H), 2.58(s, 0.7H), 3.38(q, 0.5H, J=7.00 Hz), 3.62(q, 1.5H, J=7.00 Hz), 4.32(s, 0.5H), 4.62(s, 1.5H), 4.79(s, 1.5H), 5.02(s, 0.5H), 7.41-7.43(m, 1H), 7.63-7.66(dd, 1H, J=8.40 Hz, 2.24 Hz), 7.79(s, 1H), 7.84-7.87(m, 2H), 7.89-7.90(d, 1H, J=2.24 Hz), 7.96-7.98(d, 1H, J=8.40 Hz), 8.69-8.77(m, 1H), 8.80-8.84(m, 2H).